The major long-term goal of this project is to determine the molecular mechanisms of virulence for the nontuberculous Mycobacteria (NTM). The major reservoir for NTM is municipal water systems, whereby gaining access to human hosts. Species of the Mycobacterium avium complex (MAC) infect half of AIDS patients, significantly increasing morbidity and mortality. These intracellular pathogens are the primary clinical bacterial infection for AIDS patients, and are also a source of significant nosocomial infections. The central biological question addressed is, how do NTMs, especially MAC, survive in water systems and how do they cause disease? NTM move from the hostile, nutrient- deprived environment of water systems to the likewise antagonistic location of macrophage phagosomes. The primary hypothesis is that the central prokaryotic mechanism to survive starvation, the stringent response, will be critical in the success of NTM in these two extreme environments. Knowledge gained will lead to protection of water systems from NTM contamination, and development of new therapies for those infected with NTM.